Epilepsy is a relatively widespread disease that affects approximately one million people in this country. The greatest difficulty with the treatment of epileptic patients is the lack of understanding of the cellular mechanisms that underlie recurrent seizures in the brain and the incomplete knowledge of how anticonvulsant drugs produce their effects. Previous models used to study epilepsy have concentrated on decreased GABAergic inhibition to account for epileptiform activity; but recently it has been shown that epileptiform activity can occur with intact synaptic inhibition and, therefore, some other mechanism(s) must be critical for seizure origination. We propose the hypothesis that potentiation of excitatory synaptic transmission and features of neuronal plasticity are paramount to the initiation and spread of epileptic discharges. We will test this hypothesis using voltage-clamp recording techniques and the mossy fiber-to-CA3 synapse in the in vitro hippocampal slice preparation. The goals of the proposed research are two fold: first, to investigate the cellular mechanisms underlying the large increase in synaptic efficacy during short-term posttetanic potentiation (PTP); and second, to test the hypothesis that certain anticonvulsants act through the regulation of synaptic potentiation. Experiments are designed to address the following questions: What are the physiological properties of PTP at a mixed excitatory and inhibitory cortical synapse? Does the increased synaptic efficacy during PTP involve pre- or postsynaptic changes (or both)? Do anticonvulsants regulate synaptic potentiation and network-driven epileptiform seizures in a parallel manner? Support for our hypothesis that increased excitatory synaptic efficacy could be responsible for seizure genesis as well as the site of action of certain anticonvulsant drugs would be an extremely important finding. Even partial answers to the proposed questions should aid in a better understanding of the basic mechanisms of epilepsy in the hippocampus.